Relationship between hepatocellular carcinoma development and serum viral markers in patients with undetectable serum HBV DNA level while on nucleos(t)ide analogues

Abstract

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) are risk factors for hepatocellular carcinoma (HCC) development. Linearized HBsAg kit (Lumipulse G HBsAg-Quant) is a novel assay allowing better quantification of HBsAg level. However, little is known whether they remain important for HCC development if there is profound suppression of viral replication by nucleos(t)ide analogues (NA). METHODS: Seventy-six HBV carriers who developed HCC despite undetectable serum HBV DNA (<20 IU/ml) after at least one-year NA therapy were compared with 152 matched controls who did not have HCC. Clinical and laboratory parameters were analysed in a cross-sectional manner. RESULTS: There was a significant difference in the median values of HBcrAg level between the HCC group and non-HCC group (10.2 and 1.7 kU/ml, respectively, p = 0.005), while there were no significant differences in HBsAg levels by conventional HBsAg kit and linearized HBsAg kit (Lumipulse G HBsAg-Quant). A cutoff value of HBcrAg level ≥7.8 kU/ml yielded an area under receiver operating curve (AUROC) of 0.61 (95% CI: 0.54–0.69) with a negative predictive value (NPV) of 77.0%. The odds ratio of HCC development was 3.27 (95% CI: 1.84–5.80). For the subgroup of non-cirrhotic patients, the median values of HBcrAg level of the HCC and non-HCC group were 10.2 and 1.0 kU/ml respectively (p = 0.001). A cutoff value of HBcrAg level ≥7.9 kU/ml yielded an AUROC of 0.70 (95% CI: 0.58–0.81) with a NPV of 80.6%. The odds ratio of HCC development was 5.95 (95% CI: 2.35–15.07). CONCLUSION: A higher HBcrAg level (but not HBsAg level) was associated with an increased risk of HCC development in patients who achieved undetectable serum HBV DNA while on NA therapy..